Effects of sevelamer carbonate on advanced glycation end products and antioxidant/pro-oxidant status in patients with diabetic kidney disease

Clin J Am Soc Nephrol. 2015 May 7;10(5):759-66. doi: 10.2215/CJN.07750814. Epub 2015 Feb 20.

Abstract

Background and objectives: The primary goals were to re-examine whether sevelamer carbonate (SC) reduces advanced glycation end products (AGEs) (methylglyoxal and carboxymethyllysine [CML]), increases antioxidant defenses, reduces pro-oxidants, and improves hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Secondary goals examined albuminuria, age, race, sex, and metformin prescription.

Design, setting, participants, & measurements: This two-center, randomized, intention-to-treat, open-label study evaluated 117 patients with T2DM (HbA1c >6.5%) and stages 2-4 DKD (urinary albumin/creatinine ratio ≥200 mg/g) treated with SC (1600 mg) or calcium carbonate (1200 mg), three times a day, without changing medications or diet. Statistical analyses used linear mixed models adjusted for randomization levels. Preselected subgroup analyses of sex, race, age, and metformin were conducted.

Results: SC lowered serum methylglyoxal (95% confidence interval [CI], -0.72 to -0.29; P<0.001), serum CML (95% CI, -5.08 to -1.35; P≤0.001), and intracellular CML (95% CI, -1.63 to -0.28; P=0.01). SC increased anti-inflammatory defenses, including nuclear factor like-2 (95% CI, 0.58 to 1.29; P=0.001), AGE receptor 1 (95% CI, 0.23 to 0.96; P=0.001), NAD-dependent deacetylase sirtuin-1 (95% CI, 0.20 to 0.86; P=0.002), and estrogen receptor α (95% CI, 1.38 to 2.73; P ≤0.001). SC also decreased proinflammatory factors such as TNF receptor 1 (95% CI, -1.56 to -0.72; P≤0.001) and the receptor for AGEs (95% CI, -0.58 to 1.53; P≤0.001). There were no differences in HbA1c, GFR, or albuminuria in the overall group. Subanalyses showed that SC lowered HbA1c in women (95% CI, -1.71 to -0.27; P=0.01, interaction P=0.002), and reduced albuminuria in those aged <65 years (95% CI, -1.15 to -0.07; P=0.03, interaction P=0.02) and non-Caucasians (95% CI, -1.11 to -0.22; P=0.003, interaction P≤0.001), whereas albuminuria increased after SC and calcium carbonate in Caucasians.

Conclusions: SC reduced circulating and cellular AGEs, increased antioxidants, and decreased pro-oxidants, but did not change HbA1c or the albumin/creatinine ratio overall in patients with T2DM and DKD. Because subanalyses revealed that SC may reduce HbA1c and albuminuria in some patients with T2DM with DKD, further studies may be warranted.

Keywords: advanced glycation end product; albuminuria; diabetic nephropathy; ethnicity; oxidative stress.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / blood
  • Age Factors
  • Aged
  • Albuminuria / drug therapy
  • Chelating Agents / therapeutic use*
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetic Nephropathies / blood*
  • Diabetic Nephropathies / drug therapy*
  • Dinoprost / analogs & derivatives
  • Dinoprost / blood
  • Estrogen Receptor alpha / blood
  • European Continental Ancestry Group
  • Female
  • Glycated Hemoglobin A / metabolism
  • Glycation End Products, Advanced / blood
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Intention to Treat Analysis
  • Lysine / analogs & derivatives
  • Lysine / blood
  • Male
  • Metformin / therapeutic use
  • Middle Aged
  • NF-E2-Related Factor 2 / blood
  • NF-E2-Related Factor 2 / genetics
  • Pyruvaldehyde / blood
  • RNA, Messenger / blood
  • Receptor for Advanced Glycation End Products / blood
  • Receptor for Advanced Glycation End Products / genetics
  • Receptors, Tumor Necrosis Factor, Type I / blood
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Sevelamer / therapeutic use*
  • Sex Factors
  • Single-Blind Method
  • Sirtuin 1 / blood
  • Sirtuin 1 / genetics

Substances

  • Adiponectin
  • Chelating Agents
  • Estrogen Receptor alpha
  • Glycated Hemoglobin A
  • Glycation End Products, Advanced
  • Hypoglycemic Agents
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RNA, Messenger
  • Receptor for Advanced Glycation End Products
  • Receptors, Tumor Necrosis Factor, Type I
  • hemoglobin A1c protein, human
  • 8-epi-prostaglandin F2alpha
  • N(6)-carboxymethyllysine
  • Pyruvaldehyde
  • Metformin
  • Sevelamer
  • Dinoprost
  • Sirtuin 1
  • Lysine